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J. Biol. Chem., Vol. 281, Issue 18, 12809-12816, May 5, 2006

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Parkin Protects against Mitochondrial Toxins and -Amyloid Accumulation in Skeletal Muscle Cells^*

Kenneth M. Rosen¹, Vimal Veereshwarayya, Charbel E-H. Moussa, Qinghao Fu, Matthew S. Goldberg, Michael G. Schlossmacher, Jie Shen, and Henry W. Querfurth²

From the Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135 and Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Mutations in the ubiquitin ligase-encoding Parkin gene have been implicated in the pathogenesis of autosomal recessive Parkinson disease. Outside of the central nervous system, Parkin is prominently expressed in skeletal muscle. We have found accumulations of Parkin protein in skeletal muscle biopsies taken from patients with inclusion body myositis, a degenerative disorder in which intramyofiber accumulations of the -amyloid peptide are pathognomonic. In comparing primary cultures of skeletal muscle derived from parkin knock-out and wild-type mice, we have found the absence of parkin to result in greater sensitivity to mitochondrial stressors rotenone and carbonyl cyanide 3-chlorophenylhydrazone, without any alteration in sensitivity to calcium ionophore or hydrogen peroxide. Utilizing viral expression constructs coding for the Alzheimer disease and inclusion body myositis-linked -amyloid precursor protein and for its metabolic byproducts A42 and C100, we found that parkin knock-out muscle cells are also more sensitive to the toxic effects of intracellular A. We also constructed a lentiviral system to overexpress wild-type Parkin and have shown that boosting the levels of parkin expression in normal skeletal muscle cultures provides substantial protection against both mitochondrial toxins and overexpressed -amyloid. Correspondingly, exogenous Parkin significantly lowered A levels. These data support the hypothesis that in myocytes parkin has dual properties in the maintenance of skeletal muscle mitochondrial homeostasis and in the regulation of A levels.

Received for publication, November 28, 2005 , and in revised form, February 22, 2006.

^* This work was supported in part by National Institutes of Health Grant NS041373 (to H. W. Q.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Neurology, Caritas St. Elizabeth's Medical Center, 736 Cambridge St., Boston, MA 02135. Tel.: 617-789-2674; Fax: 617-789-3111; E-mail: kenneth_rosen{at}cchcs.org.

² To whom correspondence may be addressed. Tel.: 617-789-2685; Fax: 617-789-5177; E-mail: henry.querfurth{at}tufts.edu.

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